Takeda Shintaro, Iwai Atsushi, Nakashima Mitsuko, Fujikura Daisuke, Chiba Satoko, Li Hong Mei, Uehara Jun, Kawaguchi Satoshi, Kaya Mitsunori, Nagoya Satoshi, Wada Takuro, Yuan Junying, Rayter Sydonia, Ashworth Alan, Reed John C, Yamashita Toshihiko, Uede Toshimitsu, Miyazaki Tadaaki
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Anticancer Res. 2007 Mar-Apr;27(2):761-8.
Despite improvements in chemotherapy and surgery in the treatment of osteosarcoma, satisfactory results are still difficult to achieve. New therapeutic modalities need to be developed for the improvement of these treatments. TRAIL (TNF-related apoptosis inducing ligand) is known as a selective apoptosis inducer in most tumor cells, but not in normal cells. Therefore, TRAIL is a good candidate target for the treatment of tumors. However, sensitivity of osteosarcoma cells to TRAIL-induced apoptosis is lower than that of other types of tumor cells. Recently, DAP3 (death associated protein 3) was demonstrated to play a critical role in TRAIL-mediated apoptosis through activation of pro-caspase-8. Here, we found that LKB1, a serine/threonine kinase, expressed in bone and soft tissue sarcoma cells, associated with DAP3. We also demonstrated that expression of DAP3 induced apoptosis in osteosarcoma cells. Furthermore, expression of LKB1 induced apoptosis and co-expression of LKB1 with DAP3 strongly induced apoptosis in osteosarcoma cells. In addition, expression of LKB1 kinase dead mutant, LKB1 (K78M), inhibited DAP3-induced apoptosis in these cells. These results suggest that LKB1 is critical for TRAIL-induced apoptosis induction, cooperating with DAP3 in osteosarcoma cells. It is predicted that LKB1 and DAP3 could be critical target molecules for the treatment of osteosarcomas.
尽管骨肉瘤治疗中的化疗和手术取得了进展，但仍难以获得令人满意的结果。需要开发新的治疗方法来改进这些治疗。TRAIL（肿瘤坏死因子相关凋亡诱导配体）在大多数肿瘤细胞中被认为是一种选择性凋亡诱导剂，但在正常细胞中则不然。因此，TRAIL是治疗肿瘤的一个良好候选靶点。然而，骨肉瘤细胞对TRAIL诱导的凋亡的敏感性低于其他类型的肿瘤细胞。最近，DAP3（死亡相关蛋白3）被证明通过激活前半胱天冬酶-8在TRAIL介导的凋亡中起关键作用。在此，我们发现一种在骨肉瘤细胞中表达的丝氨酸/苏氨酸激酶LKB1与DAP3相关。我们还证明DAP3的表达在骨肉瘤细胞中诱导凋亡。此外，LKB1的表达诱导凋亡，并且LKB1与DAP3的共表达在骨肉瘤细胞中强烈诱导凋亡。此外，LKB1激酶失活突变体LKB1（K78M）的表达抑制了这些细胞中DAP3诱导的凋亡。这些结果表明，LKB1在骨肉瘤细胞中与DAP3协同作用，对TRAIL诱导的凋亡诱导至关重要。预计LKB1和DAP3可能是治疗骨肉瘤的关键靶分子。
